Influenza is both a major public health threat and a NIAID bio defense category C priority pathogen. About 36,000 people die every year in the United States alone due to infection with commonly circulating influenza A viruses. Nearly 90% of these deaths are in elderly people. These deaths occur despite the fact that current influenza vaccines reach >65% of the adult population. Moreover, highly pathogenic avian H5N1 viruses cause 60% mortality in infected individuals. It is feared that a pandemic can happen at any time. Thus, there is an urgent need for an understanding of factors that influence induction of optimal influenza immunity, and for developing novel vaccination strategies that can elicit better protective immunity. These strategies should consider the age-mediated heightened susceptibility to influenza. The long-term objective of this proposal, therefore, is to both improve current vaccination strategies and contribute to the design of novel vaccination strategies to control epidemic and pandemic influenza viruses with particular regard to the elderly population. We hypothesize that age mediated effects in type-I interferon (IFN-I) induction/signaling combined with viral IFN-I evasive strategies may adversely affect influenza- specific protective immunity. This proposal tests this hypothesis and explores novel vaccination strategies for inducing RIG-I mediated type-I interferon signaling pathways during priming as means of inducing enhanced protective immunity against influenza viruses. Aim 1 examines whether age- dependent defects to influenza immunization can be minimized by interfering with viral IFN-I evasive strategies, Aim 2 tests the contribution of IFN-I signals on cells of innate immune system in generating influenza specific adaptive response, Aim 3 examines the effect of enhanced IFN-I signaling during priming on influenza-specific memory fitness, and Aim 4, explores novel vaccination strategies that enhance RIG-I mediated type-I interferon signals during priming to increase the immunogenicity, durability, and protective ability of immune response. Human epidemic and pandemic avian influenza strains will be tested in the well-characterized respiratory infection models in mice using cutting edge reagents/techniques such as TCR transgenic, knockout mice, adoptive cell transfers, bone marrow chimeras, and MHC tetramers. This knowledge not only contributes to improved vaccination strategies against influenza, especially in elderly, but also has implications for novel vaccination strategies against a variety of diseases. PUBLIC HEALTH RELEVANCE: The long-term objectives of this proposal are to design novel and improved vaccination strategies to control epidemic and pandemic influenza viruses. This knowledge will not only contribute to improved vaccination strategies against influenza, especially in elderly, but also has implications for novel vaccination strategies against a variety of diseases.